Targeted therapies for the treatment of cancer include monoclonal antibodies that bind to antigens that are expressed on tumor cells. For example, cetuximab (Erbitux®) is a monoclonal antibody that targets the epidermal growth factor receptor (EGFR, also known as ErbB1 or HER1). While such monoclonal antibodies have been shown to be effective in some patients, the response rate for targeted therapies (and for untargeted chemotherapeutics) is never 100%. For example, only about 15-20% of patients whose tumors express EGFR respond to cetuximab monotherapy. Thus, expression by a tumor of an antigen that is targeted by a therapeutic monoclonal antibody does not necessarily predict responsiveness to treatment with the antibody.
In addition to EGFR, the ErbB/HER subfamily of polypeptide growth factor receptors include the neu oncogene product ErbB2 (HER2), and the more recently identified ErbB3 (HER3) and ErbB4 (HER4) proteins. Experiments in vitro have indicated that the protein tyrosine kinase activity of the ErbB3 protein is significantly attenuated relative to that of other ErbB/HER family members. Despite its deficient kinase activity, the ErbB3 protein has been shown to be phosphorylated in a variety of cellular contexts and to play an important role in ErbB signal transduction, e.g., in cancer cells. For example, ErbB3 is constitutively phosphorylated on tyrosine residues in a subset of human breast cancer cell lines that highly express this protein.
An explanation for the phosphorylation of ErbB3 and its oncogenic impact is that, in addition to forming various active homodimers, ErbBs are cell surface receptor proteins that form heterodimeric receptor complexes that mediate ligand-dependent (and in some cases ligand-independent) activation of multiple signal transduction pathways. ErbB3, upon binding to heregulin (HRG), its primary physiological ligand, heterodimerizes more efficiently with other ErbB family members than it does in the absence of ligand. It is the fully kinase-active ErbB hetero-partner of ErbB3 in such heterodimers that is believed to phosphorylate ErbB3, promoting high levels of (potentially oncogenic) signal transduction by the heterodimer. ErbB3-containing heterodimers (such as ErbB2/ErbB3) in tumor cells have been shown to be the most mitogenic and oncogenic ErbB receptor complexes. Accordingly, ErbB3 inhibitors, including anti-ErbB3 monoclonal antibodies, are in development for use in the treatment of various cancers.
The variable response rates of patients to monoclonal antibody therapies and chemotherapies indicates that methods are needed for accurately predicting which patients are likely to respond to therapeutic treatment with such targeted and untargeted agents so that the treatment can be administered to only those patients who are likely to receive benefits that outweigh the financial costs and potential deleterious effects of treatment (including the damage to the patient due to tumor growth over time during the administration of the ineffective treatments). Particular biomarkers or sets of biomarkers (e.g., gene products such as proteins or RNAs) in tumors may be found for which a particular concentration range for each biomarker (e.g., in the set) correlates with tumor responsiveness to a particular therapy.
Accordingly, considerable efforts are being made to discover and identify characteristic biomarkers whose levels are indicative of the probability of a particular individual tumor being responsive to particular therapies. The following disclosure provides novel biomarker criteria that allow for optimization of tumor therapy using ErbB3 inhibitors, chemotherapeutic agents (such as taxanes, anti-estrogens, topoisomerase inhibitors, and nucleoside analogs) or combinations thereof, and provides additional benefits.